# 615267

HYPOGONADOTROPIC HYPOGONADISM 18 WITH OR WITHOUT ANOSMIA; HH18


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
3p14.3 Hypogonadotropic hypogonadism 18 with or without anosmia 615267 AD, AR, DD 3 IL17RD 606807
Clinical Synopsis
 
Phenotypic Series
 

INHERITANCE
- Autosomal dominant (see MISCELLANEOUS below)
- Autosomal recessive
- Digenic dominant
HEAD & NECK
Ears
- Hearing loss (in some patients)
Nose
- Hyposmia/anosmia
Teeth
- Abnormal dentition (in some patients)
GENITOURINARY
- Delayed or absent puberty
SKELETAL
- Osteopenia (in some patients)
- Osteoporosis (in some patients)
- Fractures (in some patients)
NEUROLOGIC
Central Nervous System
- Hyposmia/anosmia
ENDOCRINE FEATURES
- Delayed or absent puberty
MISCELLANEOUS
- Phenotypic variability within families and among patients carrying the same mutation appears to be due to the oligogenic nature of the disorder, with some patients having mutations in IL17RD and another neuroendocrine-related gene (e.g., FGF8 (600483), FGFR1 (136350), KISS1R (604161))
MOLECULAR BASIS
- Caused by mutation in the interleukin-17 receptor D gene (IL17RD, 606807.0001)
Hypogonadotropic hypogonadism with or without anosmia - PS147950 - 27 Entries
Location Phenotype Inheritance Phenotype
mapping key
Phenotype
MIM number
Gene/Locus Gene/Locus
MIM number
1p13.1 ?Hypogonadotropic hypogonadism 27 without anosmia AR 3 619755 NHLH2 162361
1q32.1 ?Hypogonadotropic hypogonadism 13 with or without anosmia AR 3 614842 KISS1 603286
2q14.3 {Hypogonadotropic hypogonadism 15 with or without anosmia} AD 3 614880 HS6ST1 604846
3p14.3 Hypogonadotropic hypogonadism 18 with or without anosmia AD, AR, DD 3 615267 IL17RD 606807
3p13 Hypogonadotropic hypogonadism 4 with or without anosmia AD 3 610628 PROK2 607002
4q13.2 Hypogonadotropic hypogonadism 7 without anosmia AR 3 146110 GNRHR 138850
4q24 Hypogonadotropic hypogonadism 11 with or without anosmia AR 3 614840 TACR3 162332
4q27 Hypogonadotropic hypogonadism 25 with anosmia AD 3 618841 NDNF 616506
5q31.3 Hypogonadotropic hypogonadism 17 with or without anosmia AD 3 615266 SPRY4 607984
7q21.11 {Hypogonadotropic hypogonadism 16 with or without anosmia} AD 3 614897 SEMA3A 603961
7q31.32 Hypogonadotropic hypogonadism 22, with or without anosmia AR 3 616030 FEZF1 613301
8p21.3 Hypogonadotropic hypogonadism 20 with or without anosmia AD 3 615270 FGF17 603725
8p21.2 ?Hypogonadotropic hypogonadism 12 with or without anosmia AR 3 614841 GNRH1 152760
8p11.23 Hypogonadotropic hypogonadism 2 with or without anosmia AD 3 147950 FGFR1 136350
8q12.2 Hypogonadotropic hypogonadism 5 with or without anosmia AD 3 612370 CHD7 608892
9q34.3 Hypogonadotropic hypogonadism 9 with or without anosmia AD 3 614838 NSMF 608137
10q24.32 Hypogonadotropic hypogonadism 6 with or without anosmia AD 3 612702 FGF8 600483
10q26.12 Hypogonadotropic hypogonadism 14 with or without anosmia AD 3 614858 WDR11 606417
11p14.1 Hypogonadotropic hypogonadism 24 without anosmia AR 3 229070 FSHB 136530
12q13.3 Hypogonadotropic hypogonadism 10 with or without anosmia AR 3 614839 TAC3 162330
12q21.33 Hypogonadotropic hypogonadism 19 with or without anosmia AD 3 615269 DUSP6 602748
15q21.3 Hypogonadotropic hypogonadism 26 with or without anosmia AD, AR 3 619718 TCF12 600480
19p13.3 Hypogonadotropic hypogonadism 8 with or without anosmia AR 3 614837 KISS1R 604161
19q13.33 Hypogonadotropic hypogonadism 23 with or without anosmia AR 3 228300 LHB 152780
20p12.3 Hypogonadotropic hypogonadism 3 with or without anosmia AD 3 244200 PROKR2 607123
20p12.1 Hypogonadotropic hypogonadism 21 with anosmia AD 3 615271 FLRT3 604808
Xp22.31 Hypogonadotropic hypogonadism 1 with or without anosmia (Kallmann syndrome 1) XLR 3 308700 ANOS1 300836

TEXT

A number sign (#) is used with this entry because of evidence that hypogonadotropic hypogonadism-18 with or without anosmia (HH18) is caused by heterozygous or homozygous mutation in the IL17RD gene (606807) on chromosome 3p14, sometimes in association with mutation in other genes, e.g., FGFR1 (136350) and KISS1R (604161).


Description

Congenital idiopathic hypogonadotropic hypogonadism (IHH) is a disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. Idiopathic hypogonadotropic hypogonadism can be caused by an isolated defect in gonadotropin-releasing hormone (GNRH; 152760) release, action, or both. Other associated nonreproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss, occur with variable frequency. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism has been called 'Kallmann syndrome (KS),' whereas in the presence of a normal sense of smell, it has been termed 'normosmic idiopathic hypogonadotropic hypogonadism (nIHH)' (summary by Raivio et al., 2007). Because families have been found to segregate both KS and nIHH, the disorder is here referred to as 'hypogonadotropic hypogonadism with or without anosmia (HH).'

For a discussion of genetic heterogeneity of hypogonadotropic hypogonadism with or without anosmia as well as a discussion of oligogenicity of this disorder, see 147950.


Molecular Genetics

In a cohort of 386 unrelated individuals with congenital hypogonadotropic hypogonadism (CHH), 199 of whom were anosmic and 187 normosmic, many of whom were known to harbor mutations in previously identified HH-associated genes, Miraoui et al. (2013) analyzed 7 genes involved in the FGF8 (600483)-FGFR1 (136350) network and identified 6 HH probands who were heterozygous and 2 who were homozygous for missense mutations in the IL17RD gene (see, e.g., 606807.0001-606807.0005). Two of the patients with a heterozygous IL17RD mutation also carried a heterozygous missense mutation in another HH-associated gene, FGFR1 (see 136350.0026) and KISS1R (see 604161.0007), respectively. All of the patients were anosmic, and 7 had absent puberty whereas 1 had partial puberty. Six of the 8 probands had congenital hearing loss, which was unilateral in 5 of them. The authors noted that hearing loss did not cosegregate with the IL17RD mutation in some pedigrees, indicating that although IL17RD mutations are strongly associated with anosmic HH and hearing loss, 1 allelic defect was likely not sufficient and that additional affected alleles in the same and/or other genes must be present to create the phenotype of Kallmann syndrome and hearing loss. Miraoui et al. (2013) concluded that mutations in genes encoding components of the FGF pathway are associated with complex modes of CHH inheritance and act primarily as contributors to an oligogenic genetic architecture underlying CHH.


REFERENCES

  1. Miraoui, H., Dwyer, A. A., Sykiotis, G. P., Plummer, L., Chung, W., Feng, B., Beenken, A., Clarke, J., Pers, T. H., Dworzynski, P., Keefe, K., Niedziela, M., and 17 others. Mutations in FGF17, IL17RD, DUPS6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism. Am. J. Hum. Genet. 92: 725-743, 2013. [PubMed: 23643382, images, related citations] [Full Text]

  2. Raivio, T., Falardeau, J., Dwyer, A., Quinton, R., Hayes, F. J., Hughes, V. A., Cole, L. W., Pearce, S. H., Lee, H., Boepple, P., Crowley, W. F., Jr., Pitteloud, N. Reversal of idiopathic hypogonadotropic hypogonadism. New Eng. J. Med. 357: 863-873, 2007. [PubMed: 17761590, related citations] [Full Text]


Creation Date:
Marla J. F. O'Neill : 6/4/2013
carol : 02/09/2016
alopez : 6/11/2013
alopez : 6/5/2013
alopez : 6/4/2013

# 615267

HYPOGONADOTROPIC HYPOGONADISM 18 WITH OR WITHOUT ANOSMIA; HH18


ORPHA: 478;   DO: 0090076;  


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
3p14.3 Hypogonadotropic hypogonadism 18 with or without anosmia 615267 Autosomal dominant; Autosomal recessive; Digenic dominant 3 IL17RD 606807

TEXT

A number sign (#) is used with this entry because of evidence that hypogonadotropic hypogonadism-18 with or without anosmia (HH18) is caused by heterozygous or homozygous mutation in the IL17RD gene (606807) on chromosome 3p14, sometimes in association with mutation in other genes, e.g., FGFR1 (136350) and KISS1R (604161).


Description

Congenital idiopathic hypogonadotropic hypogonadism (IHH) is a disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. Idiopathic hypogonadotropic hypogonadism can be caused by an isolated defect in gonadotropin-releasing hormone (GNRH; 152760) release, action, or both. Other associated nonreproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss, occur with variable frequency. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism has been called 'Kallmann syndrome (KS),' whereas in the presence of a normal sense of smell, it has been termed 'normosmic idiopathic hypogonadotropic hypogonadism (nIHH)' (summary by Raivio et al., 2007). Because families have been found to segregate both KS and nIHH, the disorder is here referred to as 'hypogonadotropic hypogonadism with or without anosmia (HH).'

For a discussion of genetic heterogeneity of hypogonadotropic hypogonadism with or without anosmia as well as a discussion of oligogenicity of this disorder, see 147950.


Molecular Genetics

In a cohort of 386 unrelated individuals with congenital hypogonadotropic hypogonadism (CHH), 199 of whom were anosmic and 187 normosmic, many of whom were known to harbor mutations in previously identified HH-associated genes, Miraoui et al. (2013) analyzed 7 genes involved in the FGF8 (600483)-FGFR1 (136350) network and identified 6 HH probands who were heterozygous and 2 who were homozygous for missense mutations in the IL17RD gene (see, e.g., 606807.0001-606807.0005). Two of the patients with a heterozygous IL17RD mutation also carried a heterozygous missense mutation in another HH-associated gene, FGFR1 (see 136350.0026) and KISS1R (see 604161.0007), respectively. All of the patients were anosmic, and 7 had absent puberty whereas 1 had partial puberty. Six of the 8 probands had congenital hearing loss, which was unilateral in 5 of them. The authors noted that hearing loss did not cosegregate with the IL17RD mutation in some pedigrees, indicating that although IL17RD mutations are strongly associated with anosmic HH and hearing loss, 1 allelic defect was likely not sufficient and that additional affected alleles in the same and/or other genes must be present to create the phenotype of Kallmann syndrome and hearing loss. Miraoui et al. (2013) concluded that mutations in genes encoding components of the FGF pathway are associated with complex modes of CHH inheritance and act primarily as contributors to an oligogenic genetic architecture underlying CHH.


REFERENCES

  1. Miraoui, H., Dwyer, A. A., Sykiotis, G. P., Plummer, L., Chung, W., Feng, B., Beenken, A., Clarke, J., Pers, T. H., Dworzynski, P., Keefe, K., Niedziela, M., and 17 others. Mutations in FGF17, IL17RD, DUPS6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism. Am. J. Hum. Genet. 92: 725-743, 2013. [PubMed: 23643382] [Full Text: https://doi.org/10.1016/j.ajhg.2013.04.008]

  2. Raivio, T., Falardeau, J., Dwyer, A., Quinton, R., Hayes, F. J., Hughes, V. A., Cole, L. W., Pearce, S. H., Lee, H., Boepple, P., Crowley, W. F., Jr., Pitteloud, N. Reversal of idiopathic hypogonadotropic hypogonadism. New Eng. J. Med. 357: 863-873, 2007. [PubMed: 17761590] [Full Text: https://doi.org/10.1056/NEJMoa066494]


Creation Date:
Marla J. F. O'Neill : 6/4/2013

Edit History:
carol : 02/09/2016
alopez : 6/11/2013
alopez : 6/5/2013
alopez : 6/4/2013